Improving the In Vivo Stability of [52Mn]Mn(II) Complexes with 18-Membered Macrocyclic Chelators for PET Imaging

We report the [natMn/52Mn]Mn(II) complexes of the macrocyclic chelators PYAN [3,6,10,13-tetraaza-1,8(2,6)-dipyridinacyclotetradecaphane] and CHXPYAN [(41R,42R,101R,102R)-3,5,9,11-tetraaza-1,7(2,6)-dipyridina-4,10(1,2)-dicyclohexanacyclododecaphane]. The X-ray crystal structures of Mn-PYAN and Mn-CHXPYAN evidence distorted octahedral geometries through coordination of the nitrogen atoms of the macrocycles. Cyclic voltammetry studies evidence reversible processes due to the Mn(II)/Mn(III) pair, indicating that the complexes are resistant to oxidation. CHXPYAN forms a more thermodynamically stable and kinetically inert Mn(II) complex than PYAN. Radiochemical studies with the radioactive isotope manganese-52 (52Mn, t1/2 = 5.6 days) evidenced better radiochemical yields for CHXPYAN than for PYAN. Both [52Mn]Mn(II) complexes remained stable in mouse and human serum, so in vivo stability studies were carried out. Positron emission tomography/computed tomography scans and biodistribution assays indicated that [52Mn]Mn-PYAN has a distribution pattern similar to that of [52Mn]MnCl2, showing persistent radioactivity accumulation in the kidneys. Conversely, [52Mn]Mn-CHXPYAN remained stable in vivo, clearing quickly from the liver and kidneys.


Figure S5 .
Figure S5.Plots of the linear dependence of anodic and cathodic peak currents with the square root of the scan rate for Mn-PYAN.

Figure S6 .
Figure S6.Plots of the linear dependence of anodic and cathodic peak currents with the square root of the scan rate for Mn-CHXPYAN.

Figure S12 .
Figure S12.Radio-TLC chromatograms for the stability study of [ 52 Mn]Mn-PYAN in 10 molar excess of biologically relevant metal ions.

Table S1 :
Shape analysis of the Mn(II) complexes.A value of 0 indicates that the coordination polyhedron is fully coincident with the reference polyhedron while the maximum value is 100.

Table S3 .
Crystal Data and Structure Refinement Details.

Table S5 :
Radioactivity associated with the supernatant and protein pellet upon incubation of [ 52 Mn]Mn-CHXPYAN in mouse serum at 37 ºC.

Table S6 :
Radioactivity associated with the supernatant and protein pellet upon incubation of [ 52 Mn]Mn-CHXPYAN in human serum at 37 ºC.